Neurons in the hippocampal formation and entorhinal cortex are consistently destroyed in end-stage cases of dementia of the Alzheimer type (DAT). In contrast, there is wide variation in the extent of neuron degeneration in posterior cingulate cortex and in the deposition of neurofibrillary tangles (NFT) and neuritic plaques (NP). Cases can be classified into five groups based on the layer(s) which express the most severe neuron degeneration. The laminar pattern of neuron losses, onset and length of the disease and deposition of NFT and NP are similar for each class. Experiments are proposed in postmortem tissue that will explore these hypotheses: a) laminar specificities in cingulate neuron degeneration reflect independent classes of DAT and b) alterations in muscarinic receptor binding may be associated with disruption of cholinergic and thalamocortical connections in a class-dependent manner. The four experiments are as follows. First, the sample of cases for neuron, NFT and NP densities in cingulate cortex will be expanded to 75 to enhance the reliability of this data, including determination of the age at disease onset for each class, and to determine if there is a unique group of cases with neuron degeneration mainly in layer II. Second, it has been shown that the anterior thalamic nuclei degenerate in DAT. These nuclei project to cingulate cortex and have presynaptic muscarinic receptors that can be identified in cortex with oxotremorine-M or AF-DX 116 binding. Thus, each division of this, the lateral nucleus and the medial pulvinar will be analyzed for neuron degeneration and NFT and NP to determine if there are differences within each class of the disease. Third, pilot studies show that a case from class 1 has reduced 3H-oxotremorine-M mainly in layers III-V, while in a case from class 3 binding is massively increased in layers IlIc-VI. These phenomena suggest that there may be different dynamics at work in reorganization of cingulate cortex in different classes of DAT. Thus binding of oxotremorine-M will be analyzed in at least 4 classes of this disease as will that for AF-DX 116 binding which, in the presence of unlabeled pirenzepine, is a selective protocol for presynaptic muscarinic receptors. Fourth, the laminar distribution of hemicholinium-3 binding will be analyzed to determine if there is a compensatory alteration in binding to high affinity choline uptake sites to cholinergic terminals in the layers of cases which have altered ligand binding to muscarinic receptors. The data from these studies will provide new perspectives on neuropathological subtypes of DAT and characterize new features of receptor reorganization in limbic neocortical areas.
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